Relationship Between Dental Status and Development of Osteoradionecrosis of the Jaw: a Multicenter Retrospective Study

Home , Osteoradionecrosis, Periapical periodontitis

Vol. 124 No. 2 August 2017 Relationship between dental status and development of osteoradionecrosis of the jaw: a multicenter retrospective study

Yuka Kojima, DDS,a Souichi Yanamoto, DDS, PhD,b Masahiro Umeda, DDS, PhD,b Yumiko Kawashita, DDS, PhD,c Izumi Saito, DDS,d Takumi Hasegawa, DDS, PhD,d Takahide Komori, DDS, PhD,d Nobuhiro Ueda, DDS,e Tadaaki Kirita, DDS, PhD,e Shin-ichi Yamada, DDS, PhD,f Hiroshi Kurita, DDS, PhD,f Yasuko Senga, DDS,g Yasuyuki Shibuya, DDS, PhD,g and Hiroshi Iwai, MD, PhDh

Objective. Osteoradionecrosis of the jaw is a serious late adverse event in patients with head and neck cancer undergoing radiotherapy. The aim of this study is to investigate the relationship between dental status and development of osteoradionecrosis. Study Design. Multicenter, retrospective observational study. A total of 392 patients with head and neck cancer who underwent radiotherapy were investigated for correlations between the development of osteoradionecrosis and various factors. The cumulative occurrence rate of osteoradionecrosis was calculated by the Kaplan-Meier method and analyzed by Cox regression and log-rank test. Results. Osteoradionecrosis developed in 30 of 392 patients. In 23 patients, osteoradionecrosis occurred in the mandibular molar region. A univariate analysis showed that oral or oropharyngeal cancer, jaw radiotherapy dose exceeding 50 Gy, periapical periodontitis, and tooth extraction after radiotherapy were signiﬁcantly correlated with the occurrence of osteoradionecrosis. Among these, oral and oropharyngeal cancer, periapical periodontitis, and tooth extraction after radiotherapy were signiﬁcant independent risk factors by multivariate analysis. Further, caries that occurred after radiotherapy and progressed rapidly, resulting in periapical periodontitis, carious stump, or extraction, was a major cause of osteoradionecrosis. Conclusion. Extraction of mandibular molars with periapical periodontitis before radiotherapy and strict dental management after radiotherapy may reduce the risk of osteoradionecrosis. (Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:139-145)

Radiotherapy (RT) is commonly performed in patients affected bone because it is inevitably exposed to a with head and neck cancer, but it causes various acute high dose of irradiation in most patients. Although the and late adverse effects, such as oral mucositis, xero- incidence of ORN is low, when it occurs it rarely stomia, tasting disturbance, leukocytopenia, dermatitis, cures spontaneously, and in patients with advanced and osteoradionecrosis (ORN). ORN of the jaws is a stages of ORN, surgical resection of the jaw becomes serious late complication. ORN is deﬁned as exposed necessary. This may be associated with an alteration irradiated bone that fails to heal over a period of in the shape and function of the oral cavity and the 3 months without any evidence of persisting or recur- pharynx, leading to substantial deterioration of a rent tumor.1 The mandible is the most frequently patient’s quality of life.2 Various treatment-related, tumor-related, and patient- a related risk factors of ORN have been reported, Department of Dentistry and Oral Surgery, Kansai Medical Univer- 3,4 5 sity, Osaka, Japan. including total RT dose, biologically effective dose, bDepartment of Clinical Oral Oncology, Nagasaki University Grad- combination of external beam irradiation and interstitial uate School of Biomedical Sciences, Nagasaki, Japan. brachytherapy,6 ﬁeld size,3 dose per fraction,3,5 short cPerioperative Oral Management Center, Nagasaki University Hos- interval between fractions,4,5 bone surgery in cases of pital, Nagasaki, Japan. 5 7 d post-operative irradiation, alcohol and tobacco abuse, Department of Oral and Maxillofacial Surgery, Kobe University 8,9 Graduate School of Medicine, Kobe, Japan. tumor size or stage, association of the tumor with eDepartment of Oral and Maxillofacial Surgery, Nara Medical Uni- versity, Nara, Japan. fDepartment of Dentistry and Oral Surgery, Shinshu University School of Medicine, Nagano, Japan. Statement of Clinical Relevance gDepartment of Oral and Maxillofacial Surgery, Nagoya City Uni- versity Graduate School of Medical Sciences, Nagoya, Japan. This retrospective study suggests that extraction of h e Department of Otolaryngology Head and Neck Surgery, Kansai mandibular molars with periapical periodontitis Medical University, Osaka, Japan. Received for publication Nov 17, 2016; returned for revision Feb 2, before radiotherapy and strict dental management 2017; accepted for publication Apr 19, 2017. after radiotherapy may reduce the risk of osteor- Ó 2017 Elsevier Inc. All rights reserved. adionecrosis in patients with head and neck cancer 2212-4403/$ - see front matter who undergo radiotherapy. http://dx.doi.org/10.1016/j.oooo.2017.04.012

139 ORAL AND MAXILLOFACIAL SURGERY OOOO 140 Kojima et al. August 2017

Table I. Demographic factors and oral condition of patients by development of ORN Number of patients Factor Category ORN (þ) ORN () Age <65 years 10 158 65 years 20 204 Gender Male 21 275 Female 9 87 Weight <55 kg 18 178 55 kg 12 184 Tumor site Oral cavity/oropharynx 26 193 Other 4 169 Stage I-II 6 65 III-IV 22 285 Unknown 2 12 RT method 3-D CRT 29 337 IMRT 1 25 Combination chemotherapy RT alone 12 125 CRT/BRT 18 237 Total RT dose 50-59 Gy 3 48 60 Gy 27 314 RT dose against jaw <50 Gy 2 90 50 Gy 28 272 Diabetes Present 6 88 Absent 24 274 Serum creatinine Within normal range 26 334 Higher than normal range 4 28 Serum albumin 3.0 mg/dL 28 321 <3.0 mg/dL 2 41 Minimum white blood cell count during RT 3000/mL 17 179 <3000/mL 13 183 Minimum lymphocyte count during RT 800/mL1287 <800/mL 18 275 Dental status Dentulous 30 331 Edentulous 0 31 Periapical periodontitis at first visit () 12 253 (þ) 18 109 Periapical periodontitis pre-RT () 13 294 (þ)1768 Pericoronitis at first visit () 29 357 (þ)15 Pericoronitis pre-RT () 29 360 (þ)12 Carious stump at first visit () 24 276 (þ)686 Carious stump pre-RT () 26 327 (þ)435 Severe marginal periodontitis at first visit () 20 246 (þ) 10 116 Severe marginal periodontitis pre-RT () 22 311 (þ)851 Tooth extraction before RT () 23 237 (þ) 7 125 Tooth extraction after RT () 19 335 (þ)1127 ORN, osteoradionecrosis; RT, radiotherapy; CRT, conformal radiotherapy; 3-D CRT, 3-dimensional conformal radiotherapy; IMRT, intensity- modulated radiation therapy; BRT, brachytherapy. bone,3 anatomic tumor site,8 and dental hygiene.2,10 than for those with extractions before radiation or With regard to dental status, some investigators have with no extractions at all. Thorn et al.9 found that in reported risk factors relating to the incidence of ORN. 80 patients with ORN, more than half of the cases Morrish et al.11 reported that the incidence of ORN was were initiated by tooth removal and recommended a 22 of 100 (22%) and that the risk was significantly more aggressive pre-irradiation approach to dental greater for patients who had teeth extracted after RT pathology located within the field of radiation. Raguse OOOO ORIGINAL ARTICLE Volume 124, Number 2 Kojima et al. 141

Table II. Risk factors for ORN by univariate Cox regression Factor (reference) Hazard ratio P value Age 65 years (<65 years) 1.68 (0.78-3.63) .184 Gender Male (Female) 0.85 (0.39-1.88) .690 Weight 55 kg (<55 kg) 0.63 (0.30-1.32) .217 Diabetes Yes (No) 0.89 (0.51-1.57) .689 Creatinine >Ref. value (Ref. value) 2.17 (0.75-6.26) .151 Albumin <3.0 (3.0) 0.78 (0.31-1.93) .584 Leukocyte <3,000 (3,000) 0.78 (0.38-1.61) .504 Lymphocyte <800 (800) 0.74 (0.35-1.56) .431 Primary site Oral cavity/oropharynx (other site) 4.44 (1.54-12.76) .006 Stage III-IV (I-II) 1.21 (0.48-3.02) .685 Surgery Yes (No) 1.07 (0.51-2.22) .861 RT IMRT (3-D CRT) 0.72 (0.10-5.34) .748 Chemotherapy Yes (No) 0.83 (0.40-1.73) .618 Total RT dose 60 Gy (<60 Gy) 1.64 (0.49-5.43) .420 RT dose against jaw 50 Gy (<50 Gy) 4.26 (1.01-17.91) .048 Periapical periodontitis At first visit Yes (No) 3.69 (1.74-7.81) .001 Pre-RT Yes (No) 6.28 (2.99-13.20) <.001 Pericoronitis At first visit Yes (No) 1.33 (0.18-9.80) .782 Pre-RT Yes (No) 3.95 (0.53-29.33) .180 Carious stump At first visit Yes (No) 0.81 (0.33-2.00) .652 Pre-RT Yes (No) 1.70 (0.59-4.90) .326 Severe marginal periodontitis At first visit RT Yes (No) 1.12 (0.52-2.40) .780 Pre-RT Yes (No) 2.03 (0.90-4.59) .088 Tooth extraction Pre-RT Yes (No) 0.62 (0.27-1.47) .279 Post-RT Yes (No) 4.09 (1.91-8.76) <.001 ORN, osteoradionecrosis; RT, radiotherapy; IMRT, intensity-modulated radiation therapy; 3-D CRT, 3-dimensional conformal radiotherapy.

Table III. Risk factors for ORN by multivariate Cox regression model Factor (reference) Hazard ratio (95% confidence interval) P value Primary site Oral cavity/oropharynx (other site) 3.69 (1.27-10.78) .017 RT dose against jaw 50 Gy (<50 Gy) 3.29 (0.78-13.93) .106 Periapical periodontitis before RT Yes (No) 5.13 (2.43-10.80) <.001 Tooth extraction after RT Yes (No) 3.25 (1.52-6.98) .002 ORN, osteoradionecrosis; RT, radiotherapy. et al.12 also reported that ORN developed in 38 of 139 However, there are no distinct definitions of infected patients (25.5%), and post-RT dentoalveolar surgery teeth, and dentists are often unable to decide whether to without sufficient wound closure was significantly remove a tooth. Therefore, the aims of this multicenter, correlated with the occurrence of ORN. retrospective, observational clinical study were to In 2014, National Comprehensive Cancer Network investigate the correlation between dental status and guidelines first described the principles of dental eval- development of ORN in patients with head and neck uation and management, which recommended pre-RT cancer receiving RT and to propose a new method of tooth extraction at least 2 weeks before the start of oral management for these patients. RT, if necessary.13 In contrast, Koga et al.14 reported that in 405 patients undergoing tooth extraction, 17 PATIENTS AND METHODS (4.2%) developed ORN and only 3 cases were related Patients to tooth extraction (2 before and 1 after RT). These Ethics approval by the Institutional Review Board of authors reported that the low prevalence of ORN each university was obtained. The study involved 392 suggested the possibility of performing extraction patients with head and neck cancer who underwent RT after RT by dentists experienced in the management exceeding a dose of 50 Gy between 2008 and 2014 at 6 of head and neck cancer. hospitals: Kansai Medical University, Nagasaki ORAL AND MAXILLOFACIAL SURGERY OOOO 142 Kojima et al. August 2017

Fig. 1. Kaplan-Meier curve of the incidence of osteoradionecrosis. A, primary site; B, periapical periodontitis; C, tooth extraction after radiotherapy.

University, Kobe University, Nara Medical University, extraction after RT. Correlations between these factors Shinshu University, and Nagoya City University. All and development of ORN were analyzed statistically. patients underwent pre-operative dental evaluation, panorama X-ray examination, extraction of infected Clinical characteristics of patients who developed teeth as much as possible, and oral health care (tooth osteoradionecrosis brushing, removal of dental calculus, and professional Clinical features and panorama X-ray ﬁndings at the mechanical teeth cleaning) before RT. Those who were occurrence of ORN were examined in patients who not followed up at least for 1 year were excluded from developed ORN, and the possible triggers of ORN were the study. investigated.

Variables Statistical analysis Various clinical factors and the occurrence of ORN were Statistical analyses were performed using SPSS soft- examined retrospectively, including (1) demographic ware (version 22.0; SPSS Japan IBM, Tokyo, Japan). factors: age, gender, weight; (2) general condition: dia- The cumulative occurrence rate of ORN was calculated betes, serum creatinine before RT, serum albumin by the Kaplan-Meier method and analyzed by Cox before RT, minimum white blood cell count during RT, regression and log-rank test. and minimum lymphocyte count during RT; (3) tumor factors: site and stage; (4) treatment factors: RT method, total RT dose, RT dose against jaw, and combination RESULTS chemotherapy; and (5) dental factors: dental status Patient demographic and baseline characteristics (dentulous/edentulous) and periapical periodontitis Demographic factors and oral condition of patients by diagnosed by panorama X-ray at the first visit and pre- development of ORN are presented in Table I. Of 392 RT, severe marginal periodontitis at the first visit and patients, 296 were male and 96 were female. The pre-RT, pericoronitis at the first visit and pre-RT, ages of patients ranged from 24 to 90 years old, with carious stump leaving only the tooth root at the first an average of 66 years. The most frequent tumor site visit and pre-RT, tooth extraction before RT, and tooth was oral cavity, followed by hypopharynx/larynx and OOOO ORIGINAL ARTICLE Volume 124, Number 2 Kojima et al. 143

Table IV. Cause of ORN in each patient Duration from finish of RT to development Case Tumor site of ORN (months) Site of ORN Cause of ORN 1 Oropharynx 3 Mandibular molar Spontaneous 2 Oral cavity 5 Maxillary canine Progressive caries ➝ extraction 3 Oral cavity 5 Mandibular molar Spontaneous 4 Oral cavity 5 Mandibular molar Spontaneous 5 Oral cavity 6 Mandibular molar Periapical periodontitis 6 Maxillary sinus 7 Maxillary molar Bone surgery 7 Oral cavity 8 Mandibular molar Progressive caries ➝ extraction 8 Oral cavity 9 Maxillary molar Bone surgery 9 Oral cavity 10 Mandibular incisor Progressive caries ➝ periapical periodontitis 10 Oral cavity 14 Maxillary canine Progressive caries ➝ extraction 11 Oral cavity 15 Mandibular molar Marginal periodontitis 12 Other 16 Mandibular molar Periapical periodontitis 13 Oral cavity 16 Maxillary molar Periapical periodontitis 14 Oral cavity 16 Mandibular molar Marginal periodontitis/extraction 15 Oropharynx 16 Mandibular molar Periapical periodontitis 16 Nasopharynx 24 Maxillary molar Marginal periodontitis 17 Oral cavity 25 Mandibular molar Periapical periodontitis 18 Oral cavity 30 Mandibular molar Ext before RT 19 Oral cavity 32 Mandibular molar Spontaneous 20 Oropharynx 33 Mandibular molar Marginal periodontitis 21 Maxillary sinus 34 Mandibular molar Periapical periodontitis 22 Oropharynx 34 Mandibular molar Periapical periodontitis 23 Oropharynx 36 Mandibular molar Progressive caries ➝ periapical periodontitis 24 Oral cavity 41 Mandibular molar Progressive caries ➝ carious stump 25 Oral cavity 45 Mandibular molar Periapical periodontitis 26 Oropharynx 51 Mandibular molar Spontaneous 27 Oropharynx 54 Mandibular molar Progressive caries ➝ extraction 28 Oral cavity 57 Mandibular molar Progressive caries ➝ carious stump 29 Oral cavity 58 Mandibular molar Progressive caries ➝ periapical periodontitis 30 Oral cavity 96 Mandibular molar Spontaneous ORN, osteoradionecrosis; RT, radiotherapy. oropharynx. More than 80% of the patients had an oropharyngeal cancer; RT dose to the jaw exceeding advanced tumor stage. With regard to the RT method, 50 Gy, periapical periodontitis at the first visit and pre- 366 patients underwent conventional 3-dimensional RT, and tooth extraction after RT were significantly conformal radiotherapy, whereas 26 underwent correlated with occurrence of ORN (Table II). Size of intensity-modulated radiation therapy. The average to- periapical radiolucent lesion was not correlated with tal dose of RT was 63.5 Gy. development of ORN. A multivariate analysis showed At the first visit, 127 patients had teeth with peri- that oral or oropharyngeal cancer (hazard ratio [HR]: apical periodontitis, 6 had pericoronitis, 92 had carious 3.69, 95% confidence interval [CI]: 1.27-10.78), stump, and 126 had severe marginal periodontitis. In periapical periodontitis pre-RT (HR: 5.13, 95% CI: these cases, tooth extraction was carried out as much as 2.43-10.80), and tooth extraction after RT (HR: 3.25, possible, although some teeth were preserved for 95% CI: 1.52-6.98) were independent risk factors for various reasons, such as absence of symptoms, patient ORN (Table III). The cumulative occurrence rates of disagreement, or limited time to start RT. At the start of ORN by primary site, periapical periodontitis pre-RT, RT, 85 patients had periapical periodontitis, 3 had and tooth extraction after RT are shown in Figure 1. pericoronitis, 59 had severe carious stump, and 53 had severe marginal periodontitis. Tooth extraction before RT was performed in 132 patients, while extraction Clinical characteristics of patients who developed after RT was performed in 38 patients. osteoradionecrosis Table IV shows the characteristics of patients who developed ORN. ORN occurred between 3 and Factors affecting development of 96 months (median 20 months) after RT. No osteoradionecrosis edentulous patients developed ORN. Twenty-three of ORN occurred in 30 of 392 patients (7.7%). A uni- 30 patients developed ORN in the molar region of the variate analysis revealed variables of oral or lower jaw, whereas 4 developed it in the molar region ORAL AND MAXILLOFACIAL SURGERY OOOO 144 Kojima et al. August 2017 of the upper jaw, 2 in the canine of the upper jaw, and 1 healthy before RT; however, dental caries occurred after in the incisor of the lower jaw. The probable cause of RT and progressed rapidly. Strict dental management ORN was periapical periodontitis in 8 patients and se- after RT, including frequent evaluation by a dentist and vere marginal periodontitis in 4 patients (after tooth topical fluorine administration, in addition to imple- extraction post-RT in 1 patient); however, ORN did not mentation of a pre-RT dental procedure, is necessary to develop in teeth with carious stump or pericoronitis prevent ORN. We are now conducting a prospective before RT. Further, 9 patients developed ORN from a study on the efficacy of topical fluoride application at healthy tooth before RT, but dental caries occurred and night using a spacer, which is a silicone guard, to progressed rapidly after RT, resulting in periapical minimize radiation backscatter for the prevention of periodontitis in 3 patients, carious stump in 2, and tooth progressive caries after RT. extraction in 4. CONCLUSIONS DISCUSSION The results of this retrospective study reveal that oral There are many reports on the relationship between and oropharyngeal cancer, periapical periodontitis, and tooth extraction and development of ORN. In contrast, tooth extraction after radiotherapy are independent risk 14 Koga et al. reported that in 405 patients undergoing factors for ORN. These findings may assist in the tooth extraction, 17 patients developed ORN and only management of patients with head and neck cancer 15 3 were related to tooth extraction. Chang et al. undergoing RT regarding ORN prevention. Large-scale concluded that pre-RT tooth extraction did not reduce prospective studies are required in the future. the risk of ORN in 413 patients with oropharyngeal cancer treated with RT. Although consensus on the risk of tooth extraction after RT is lacking, many authors REFERENCES 1. Marx RE. Osteoradionecrosis: a new concept of its pathophysi- believe pre-RT tooth extraction may reduce the fre- ology. J Oral Maxillofac Surg. 1983;41:283-288. quency of ORN. However, although important, pre-RT 2. Jereczek-Fossa BA, Orecchia R. Radiation-induced mandibular tooth extraction recommendations are not what most bone complications. Cancer Treat Rev. 2002;28:65-74. clinicians need to know; instead, most clinicians are 3. Glanzmann C, Gratz KW. Radionecrosis of the mandible: a keen to know which teeth should be extracted. There- retrospective analysis of the incidence and risk factors. Radiother Oncol. 1995;36:94-100. fore, this multicenter retrospective observational study 4. Withers RH, Peters LJ, Taylore JMG, et al. Late normal tissue was conducted to establish indications of tooth extrac- sequelae from radiation therapy for carcinoma of the tonsil: tion by investigating the relationship between dental patterns of fractionation study of radiobiology. Int J Radiat Oncol status and the development of osteoradionecrosis. Biol Phys. 1995;33:563-568. Findings indicate that periapical focus pre-RT is an 5. Niewald M, Barbie O, Schnabel K, et al. Risk factors and dose effect relationship for osteoradionecrosis after hyperfractionated independent risk factor for the development of ORN. and conventionally fractionated radiotherapy for oral cancer. Considering the fact that most cases of ORN occur in Br J Radiol. 1996;69:847-851. the molar region of the lower jaw, the mandibular 6. Miura M, Takeda M, Sasaki T, et al. Factors affecting mandibular molar, with periapical focus, may need to be extracted complications in low dose rate brachytherapy for oral tongue or have root canal treatment performed, regardless of carcinoma with special reference to spacer. Int J Radiat Oncol Biol Phys. 1998;41:763-770. the size of the periapical radiolucent area. Further, tooth 7. Kluth EV, Jain PR, Stuchell RN, Frich JC. A study of factors extraction after RT is also significantly correlated with contributing to the development of osteoradionecrosis of the jaws. the development of ORN. This suggests that teeth that J Prosthet Dent. 1988;59:194-201. cannot be preserved for a long time should be extracted 8. Murray CG, Herson J, Daly TE, Zimmerman S. Radiation ne- fl before the start of RT. crosis of the mandible: a 10 year study. Part I. Factors in u- encing the onset of the necrosis. Int J Radiat Oncol Phys. 1980;6: Dental management after RT is important in the 16 543-548. prevention of ORN. Katsura et al. reported that oral 9. Thorn JJ, Hansen HS, Specht L, Bastholt L. Osteoradionecrosis of health status before RT was not a significant risk factor the jaws: clinical characteristics and relation to the field of irra- for ORN, while oral status after RT was significantly diation. J Oral Maxillofac Surg. 2000;58:1088-1093. associated with the development of ORN. Although 10. Madrid C, Abarca M, Bouferrache K. Osteoradionecrosis: an update. Oral Oncol. 2010;46:471-474. their study was based on only a few patients, it 11. Morrish RB Jr, Chan E, Silverman S Jr, Meyer J, Fu KK, highlighted the importance of oral management after Greenspan D. Osteonecrosis in patients irradiated for head and 17 RT. Kobayashi et al. also stated that implementing a neck carcinoma. Cancer. 1981;47:1980-1983. radiation caries prevention program after RT is crucial 12. Raguse JD, Hossamo J, Tinhofer I, et al. Patient- and treatment- to control ORN in oral cancer patients undergoing related risk factors for osteoradionecrosis of the jaw in patients with head and neck cancer. Oral Surg Oral Med Oral Pathol Oral intra-arterial and conventional intravenous concurrent Radiol. 2016;121:215-221. chemoradiotherapy. In the present study, 9 of 30 patients 13. National Comprehensive Cancer Network clinical practice developed ORN in the region where a tooth had been guidelines in oncology (NCCN guidelines). Head and neck OOOO ORIGINAL ARTICLE Volume 124, Number 2 Kojima et al. 145

cancers version 1. 2016. Available at: https://www.nccn.org/ 17. Kobayashi W, Teh BG, Kimura H, Kakehata S, Kawaguchi H, professionals/physician_gls/pdf/head-and-neck.pdf. Accessed Takai Y. Comparison of osteoradionecrosis of the jaw after August 24, 2016. superselective intra-arterial chemoradiotherapy versus conven- 14. Koga DH, Salvajoli JV, Kowalski LP, Nishimoto IN, tional concurrent chemoradiotherapy of oral cancer. J Oral Alves FA. Dental extractions related to head and neck Maxillofac Surg. 2015;73:994-1002. radiotherapy: ten-year experience of a single institution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105: Reprint requests: e1-e6. 15. Chang DT, Sandow PR, Morris CG, et al. Do pre-irradiation Yuka Kojima, DDS dental extractions reduce the risk of osteoradionecrosis of the Department of Dentistry and Oral Surgery mandible? Head Neck. 2007;29:528-536. Kansai Medical University 16. Katsura K, Sasai K, Sato K, Saito M, Hoshina H, Hayashi T. 2-3-1, Shinmachi Relationship between oral health status and development of Hirakata osteoradionecrosis of the mandible: A retrospective longitudinal Osaka 573-1191 study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Japan 2008;105:731-738. [email protected]